Abstract

Aim

Limited treatment options are available for patients with BRAF wildtype and NRAS mutant metastatic melanoma. Paclitaxel has modest activity as monotherapy in melanoma. ERK is constitutively activated in melanoma regardless of BRAF mutational status and this leads to degradation of pro-apototic proteins, hypothesized to result in resistance to paclitaxel. Trametinib is a highly selective allosteric MEK inhibitor that effectively suppresses ERK. The combination of trametinib and paclitaxel is therefore potentially synergistic and explored in this phase 1 trial.

Methods

Eligible patients had advanced melanoma, known BRAF (wildtype and mutant both eligible) and NRAS status, a maximum of two prior lines of systemic therapy and a performance status of 0 or 1. Patients received trametinib daily in escalating doses with a fixed dose of weekly paclitaxel (80mg/m2, given three weeks of four). The trametinib dose was capped at 2.0mg daily (the maximum tolerated dose (MTD) from earlier monotherapy studies).